Epilepsia, 48(Suppl. 5):79–85, 2007 Blackwell Publishing, Inc. C  International League Against Epilepsy Immature Neurons and GABA Networks May Contribute to Epileptogenesis in Pediatric Cortical Dysplasia ∗ Carlos Cepeda, ∗ V´ eronique M. Andr´ e, ∗ Nanping Wu, ∗ Irene Yamazaki, ∗ Besim Uzgil, ‡Harry V. Vinters, ∗ Michael S. Levine, and †Gary W. Mathern ∗ Mental Retardation Research Center, †Division of Neurosurgery, and ‡Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, California, U.S.A. Summary: Cortical dysplasia (CD), a frequent pathological substrate of pediatric epilepsy surgery patients, has a number of similarities with immature cortex, such as reduced Mg 2+ sensitivity of N-methyl-D-aspartate (NMDA) receptors and the persistence of subplate-like neurons and undifferentiated cells. Because γ -aminobutyric acid (GABA) is the main neurotrans- mitter in early cortical development, we hypothesized increased GABA receptor-mediated synaptic function in CD tissue. In- frared videomicroscopy and whole-cell patch clamp recordings were used to characterize the morphology and electrophysio- logical properties of immature and normal-appearing neurons in slices from cortical tissue samples resected for the treatment of pharmacoresistant epilepsy in children (0.2–14 years). In addi- tion, we examined spontaneous and evoked synaptic activity, as well as responses to exogenous GABA application. We demon- strate both the presence of immature pyramidal neurons and networks in young CD tissue and the predominance of GABA synaptic activity. In addition, spontaneous GABA depolariza- tions frequently induced action potentials, supporting a poten- tial excitatory role of GABA in CD. Evoked synaptic responses mediated by GABA were also prominent, and bath application of 4-aminopyridine induced rhythmic depolarizations that were blocked by bicuculline. Finally, responses to exogenous appli- cation of GABA had depolarized reversal potentials in severe compared to mild and non-CD cases. The present data sup- port the hypothesis that CD shares features of immature cortex, with predominant and potentially excitatory GABA A receptor- mediated neurotransmission. These results could partially ex- plain the increased excitability of the cortical network in pediatric CD. Key Words: Cortical Dysplasia—Pediatric epilepsy— Immature neurons—GABA. Cortical dysplasia (CD), one of the most common pathological substrates in pediatric epilepsy surgery pa- tients (Mathern et al., 1999), is characterized by dyslami- nation, ectopic white matter neurons, and in severe cases, the presence of cytomegalic neurons and balloon cells in the most affected areas (Taylor et al., 1971; Mischel et al., 1995). The causes of CD are still unknown but may in- volve multiple factors, from extrinsic damage during cor- tical development to genetic polymorphisms (Crino et al., 2002). At least two main types of CD have been recog- nized, a mild form (CD I, according to Palmini et al., 2004) with lack of normal stratification of cortical layers, but no dysplastic cells, and a more severe form associ- ated with cytomegalic neurons and balloon cells (CD IIA and B). Whereas cortical dyslamination could be the con- sequence of improper neuronal migration, the origin of dysplastic cells is still unclear. Recently, we hypothesized Address correspondence and reprint requests to Carlos Cepeda, Ph.D., MRRC, NPI room 58-258, UCLA School of Medicine, Los Angeles, CA 90024, U.S.A. E-mail: ccepeda@mednet.ucla.edu doi: 10.1111/j.1528-1167.2007.01293.x that balloon cells could result from abnormal differentia- tion of radial glia, whereas cytomegalic neurons could be retained subplate-like cells (Cepeda et al., 2003; Andres et al., 2005). In a previous study we characterized morphologically and electrophysiologically the abnormal cell types in se- vere CD, in particular the cytomegalic neurons and balloon cells (Cepeda et al., 2003). In addition, we demonstrated the presence of clusters of immature-looking pyramidal neurons. These cells were frequently present in the most abnormal areas of severe CD, in the vicinity of cytome- galic pyramidal neurons, but they also were present in mild CD cases. Furthermore, we demonstrated reduced Mg 2+ sensitivity of N-methyl-D-aspartate (NMDA) receptors, a sign of cellular immaturity (Andr´ e et al., 2004), suggesting that CD tissue has developmental alterations. A normal feature of immature neuronal networks is the predominance of GABAergic synaptic inputs, which can be depolarizing and induce cell firing (Cherubini et al., 1991). In the present study we show that immature and also some normal-appearing pyramidal cells from severe CD cases retain immature inputs with GABA, not glutamate, 79